Polymer Simulations of Heteromorphic Chromatin Predict the 3D Folding of Complex Genomic Loci.-猫眼课题宝

DOI：

10.1016/j.molcel.2018.09.016

发表时间：

2018-11-15

期刊：

Molecular cell

影响因子：

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

Buckle A;Brackley CA;Boyle S;Marenduzzo D;Gilbert N

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242782/

折叠成3D大分子结构的染色质通常通过染色体构象捕获（3C）和荧光原位杂交（FISH）技术来分析，但这些技术经常提供矛盾的结果。染色质可以被建模为由连接的单元链组成的简单聚合物。通过嵌入表观遗传标记（H3 K27 ac）的数据，（使用测序[ATAC-seq]测定转座酶可接近的染色质）和结构锚（CCCTC-结合因子[CTCF]），我们建立了一个高度预测的异形聚合物（HiP-HoP）模型，其中染色质纤维沿其长度沿着变化;结合扩散蛋白质桥和环挤出，该模型预测了群体和单细胞水平上基因组位点的3D组织。该模型在几个基因位点进行了验证，包括复杂的Pax 6基因，并且能够确定具有不同转录活性水平的细胞类型的位点构象，并解释增强子使用的不同机制。表观遗传标记的最小先验知识足以在3D中概括复杂的基因组位点，并能够预测染色质折叠路径。HiP-HoP：高预测性异形聚合物模型分析染色质结构聚合物模拟使用广泛可用的表观遗传和蛋白质结合数据作为输入使用3D FISH和Capture-C模拟的复杂基因座的HiP-HoP模型揭示了染色质纤维折叠中惊人的构象变异性Buckle et al.开发一个高度预测性的异形聚合物（HiP-HoP）模型，该模型使用表观遗传和蛋白质结合数据来预测3D染色质组织，并通过FISH和Capture-C实验进行验证。这些模拟显示了细胞群内纤维折叠的惊人构象变异性，并可以解释增强子使用的不同机制。

Chromatin folded into 3D macromolecular structures is often analyzed by chromosome conformation capture (3C) and fluorescence in situ hybridization (FISH) techniques, but these frequently provide contradictory results. Chromatin can be modeled as a simple polymer composed of a connected chain of units. By embedding data for epigenetic marks (H3K27ac), chromatin accessibility (assay for transposase-accessible chromatin using sequencing [ATAC-seq]), and structural anchors (CCCTC-binding factor [CTCF]), we developed a highly predictive heteromorphic polymer (HiP-HoP) model, where the chromatin fiber varied along its length; combined with diffusing protein bridges and loop extrusion, this model predicted the 3D organization of genomic loci at a population and single-cell level. The model was validated at several gene loci, including the complex Pax6 gene, and was able to determine locus conformations across cell types with varying levels of transcriptional activity and explain different mechanisms of enhancer use. Minimal a priori knowledge of epigenetic marks is sufficient to recapitulate complex genomic loci in 3D and enable predictions of chromatin folding paths. HiP-HoP: highly predictive heteromorphic polymer model to analyze chromatin structure Polymer simulations use widely available epigenetic and protein binding data as input Validate HiP-HoP model at complex loci using 3D FISH and Capture-C Simulations uncover striking conformational variability in chromatin fiber folding Buckle et al. develop a highly predictive heteromorphic polymer (HiP-HoP) model that uses epigenetic and protein binding data to predict 3D chromatin organizations, validated by FISH and Capture-C experiments. These simulations show striking conformation variability in fiber folding within a cell population and can explain different mechanisms of enhancer use.